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Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice.

Drug metabolism and disposition: the biological fate of chemicals (2014-04-26)
Yuki Kutsuno, Tomoo Itoh, Robert H Tukey, Ryoichi Fujiwara
ABSTRACT

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and drug-induced toxicity in humans.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Potassium phosphate tribasic, reagent grade, ≥98%
Sigma-Aldrich
Ibuprofen, ≥98% (GC)
Supelco
Ibuprofen, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Diclofenac sodium salt
Supelco
Diclofenac sodium salt, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Diclofenac sodium salt, analytical standard
Ibuprofen for peak identification, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Uridine 5′-diphosphoglucuronic acid ammonium salt, 98-100%
Supelco
Ibuprofen
USP
Ibuprofen, United States Pharmacopeia (USP) Reference Standard
USP
Diclofenac sodium, United States Pharmacopeia (USP) Reference Standard
Ibuprofen, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Ibuprofen, meets USP testing specifications
Diclofenac for system suitability, European Pharmacopoeia (EP) Reference Standard
Diclofenac sodium, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Etodolac
Etodolac for peak identification, European Pharmacopoeia (EP) Reference Standard
Etodolac, European Pharmacopoeia (EP) Reference Standard

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